<p>Proprotein convertase subtilisin-kexin type 9 (PCSK9) has recently emerged as a significant mediator that links metabolic dysfunction to neurodegeneration related to Alzheimer’s disease (AD). It is a well-known and crucial component involved in cholesterol homeostasis. However, its function in the central nervous system (CNS) is still in its early stages. Normally, it is engaged with the breakdown of cholesterol in the body, but within the brain, PCSK9 has been seen to disrupt the homeostasis of cholesterol and its uptake. Receptors such as LDL receptor-related protein-1 (LRP-1) and low-density lipoprotein receptor (LDLR) are crucial for the survival of neurons, as they are responsible for the clearance of amyloid-β (Aβ) and peripheral lipid control. Elevated PCSK9 activity may promote degradation of these receptors, which eventually leads to deposition of Aβ near synapses along with reduced uptake of cholesterol by neurons, which may contribute to neurotoxicity and neuronal dysfunction. This review aims to explore the effect of elevated PCSK9 levels on the development as well as exacerbation of AD via different molecular mechanisms. Along with cholesterol dyshomeostasis, PCSK9 is found to be involved in glucose dysregulation, mechanistic target of rapamycin (mTOR) dysregulation, increased oxidative stress, neuroinflammation, reduced neurogenesis, affected Wnt-β-catenin signaling, and cholinergic signaling. Together, these mechanisms may contribute to AD progression. Preclinical studies show that pharmacological therapies targeting PCSK9 can give promising results by reducing neuroinflammation, modulating lipid homeostasis, and lowering Aβ accumulation. Therefore, modulation of PCSK9 represents a promising therapeutic strategy that warrants further mechanistic and clinical investigation in AD.</p> Graphical Abstract <p></p>